ADA 2025: Oral Semaglutide Demonstrates Cardiovascular Benefits in SOUL Trial

Author(s):

Kennedy Ferruggia, Assistant Editor

Fact checked by:

Luke Halpern, Assistant Editor

Key Takeaways

Oral semaglutide reduced MACE by 14% in high-risk type 2 diabetes patients, showing significant cardiovascular benefits.
The trial demonstrated consistent benefits across diverse populations, including those using SGLT2 inhibitors, with a favorable safety profile.
Experts emphasized oral semaglutide as a promising alternative to injectable GLP-1 receptor agonists for managing diabetes and cardiovascular risk.
The benefits were more pronounced in patients with higher baseline A1C levels, with no new adverse signals reported.

Oral semaglutide shows promising cardiovascular benefits for type 2 diabetes patients, reducing major adverse events by 14% in the SOUL trial.

Oral semaglutide demonstrated significant cardiovascular benefits for patients with type 2 diabetes (T2D) and high cardiovascular (CV) risk in the SOUL trial, reducing major adverse cardiovascular events (MACE) by 14%. The findings from this double-blind, placebo-controlled, phase 3b trial were shared during a panel discussion titled “SOUL Trial—Effects of Oral Semaglutide on Cardiovascular (and Other) Outcomes in People with Type 2 Diabetes at High CV Risk,” presented at the 85th Scientific Sessions of the American Diabetes Association (ADA) in Chicago, Illinois, held June 20 to 23, 2025.^1,2

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Results revealed that the oral glucagon-like peptide-1 receptor agonist (GLP-1 RA) lowered the risk of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke across diverse patient populations.^1,2

“When treating patients with type 2 diabetes, it’s also important to address dangerous comorbidities such as the risk of heart disease,” said Darren K. McGuire, MD, MHSc, professor of medicine at UT Southwestern Medical Center and lead author of the study, in a news release. “Our findings indicate that oral semaglutide could be a promising option for treating both diabetes and cardiovascular risk.”²

The expert panel featured McGuire; Rodica Pop-Busui, MD, PhD, Oregon Health & Science University; Nikolaus Marx, MD, FESC, FAHA, RWTH Aachen University; John B. Buse, MD, PhD, University of North Carolina School of Medicine; Silvio E. Inzucchi, MD, Yale School of Medicine; and John Deanfield, MB, BChir, FRCP, FESC, FACC, University College London. In the discussion, the experts suggested that oral semaglutide could offer a more accessible alternative to injectable GLP-1 receptor agonists.¹

SOUL Trial Design and Results

Overview and Baseline Characteristics

McGuire began the discussion by recapping outcomes from the SOUL trial, which were published in New England Journal of Medicine in March 2025. The study was designed to assess the efficacy of oral semaglutide in individuals with T2D and established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both.^1,2

“If it wasn't clear, we weren’t testing just semaglutide—we were testing whether we can get enough medication through the GI tract to mimic the GLP-1 injectable,” McGuire said. “This was for people who had an indication for GLP-1 but, for whatever reason, were not being prescribed an injectable.”¹

The trial enrolled 9650 individuals aged 50 years and older, with an A1C level between 6.5% and 10%. Participants were randomly assigned to receive once-daily oral semaglutide or placebo with standard care at doses of 3 mg, 7 mg, or 14 mg.^1,2

End Points and Outcomes

The primary end point was time to first occurrence of a major cardiovascular event, defined as death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included major kidney disease events based on a 5-point composite, as well as major adverse limb events.^1,2

Initial results demonstrated a 14% reduction in MACE with oral semaglutide. Specifically, MACE occurred in 579 of 4,825 individuals in the semaglutide group, compared to 668 of 4825 in the placebo group, yielding a hazard ratio of 0.88.^1,2

While confirmatory secondary outcomes showed no statistically significant differences between groups, Pop-Busui shared that serious adverse events occurred in 47.9% of the semaglutide group compared to 50.3% in the placebo group. Gastrointestinal disorders were reported in 5.0% and 4.4% of participants, respectively.^1,2

“The overall safety profile of oral semaglutide in SOUL was consistent with what was seen in previous trials, and we did not observe any new signals,” Pop-Busui said.¹

Combination Therapy with SGLT2 Inhibitors

Marx expanded on the efficacy and safety of oral semaglutide when used with or without sodium-glucose cotransporter-2 inhibitors (SGLT2i). Among the 9650 participants, 2596 were using SGLT2i at baseline, and 4718 used SGLT2i at any time during the trial.¹

Oral semaglutide reduced MACE outcomes regardless of concomitant SGLT2i treatment. Marx noted that the safety profiles of semaglutide were similar with or without SGLT2i use. There was no significant difference in the incidence of severe hypoglycemia between participants with SGLT2i at baseline (5.9% vs 6.5%) and those without (2.2% vs 2.4%). Likewise, the incidence of ketoacidosis was comparable: 0.6% vs 0.5% (with SGLT2i) and 0.2% vs 0.2% (without SGLT2i).¹

“These findings provide clinicians further confidence to combine GLP-1 receptor agonists and SGLT2i with the aim of reducing cardiovascular events in this high-risk population,” Marx concluded.¹

HbA1C and BMI Outcomes

In a subgroup analysis, SOUL evaluated cardiovascular outcomes by participants’ A1C levels, body mass index (BMI), and body weight at baseline. Buse noted that cardiovascular outcomes were also analyzed based on changes in these variables at week 52.¹

“It's a little hard to operationalize this heterogeneity in the meta-analysis because of the wide range of A1C cut points,” Buse said. “It’s difficult to determine an A1C threshold at which you might change your mind about whether to use a GLP-1 receptor agonist to manage cardiovascular risk.”¹

Post hoc results revealed consistent cardiovascular benefits across all BMI baseline categories, with more pronounced benefits in participants who had higher A1C levels at baseline. Buse noted that further details would be presented at ADA.¹

Stroke Outcomes

Inzucchi presented the stroke outcomes assessed in SOUL, noting that diabetes doubles stroke risk, especially in the presence of elevated A1C. While oral semaglutide reduced MACE by 14%, the reduction in stroke alone was not statistically significant. However, Inzucchi suggested that younger patients and those without hypertension may benefit from semaglutide for stroke prevention.¹

Among participants with prior stroke, there was no significant reduction in recurrent stroke; however, the group experienced a 56% reduction in myocardial infarction. The most recent meta-analysis showed a stroke treatment effect estimate of 0.86 for GLP-1 receptor agonists, aligning with overall MACE benefits.¹

“Based on the totality of evidence regarding cardiovascular benefits of GLP-1 receptor agonists, the 2021 American Heart Association stroke guidelines remain valid for antidiabetic therapy in patients with T2D and stroke,” Inzucchi concluded.¹

Conclusion

Results from the SOUL clinical trial demonstrate consistent cardiovascular benefits with oral semaglutide in patients with or without SGLT2 inhibitor therapy. The benefits were more pronounced in patients with higher baseline A1C levels. The safety profile remained favorable, with no new adverse signals reported. Experts emphasized the importance of translating these findings into real-world practice to advance clinical care in high-risk patients with T2D.^1,2